Acute lymphoblastic leukaemia or ALL is a blood cancer that affects a type of white blood cell called lymphocytes. — Wikimedia Commons
In conjunction with Childhood Cancer Awareness month, we celebrate the progress made in treating acute lymphoblastic leukaemia (ALL), the commonest childhood cancer.
Every year, one in 25,000 children are diagnosed with ALL worldwide.
In Malaysia, it is estimated that 500 children are diagnosed annually with ALL.
Indeed, the race to cure childhood ALL is one made for the movies.
From a universally fatal disease in the 1960’s, now over 85% of children with ALL are cured.
This achievement has been possible due to the perseverance and discoveries by pioneers such as Sydney Farber and Don Pinkel.
When former United States President, the late Richard Nixon launched the War Against Cancer Program in 1971, many effective cytotoxic agents from a variety of sources were discovered.
These included flowers (vincristine from periwinkle), bacteria (daunorubicin from Streptomyces species) and even a Caribbean sea sponge (cytarabine from Tectitethya crypta)!
Notably, all these drugs are now on the World Health Organization’s (WHO) List of Essential Medicines.
The 1970’s also saw the start of multi-institution ALL clinical trials, where these chemotherapy agents were used in various combinations to achieve cure.
This is akin to a maestro arranging the instruments in his orchestra to achieve a musical masterpiece.
It is certainly remarkable that great leaps in survival from ALL has been accomplished using permutations of the same drugs.
Enzyme discovery
A key drug in the successes of ALL treatment in both children and adults is asparaginase.
Asparaginase, an enzyme with cytotoxic activity, was discovered by John Kidd in 1953 whilst experimenting with various proteins to treat carcinoma in rabbits.
Asparaginase acts by depleting the amino acid asparagine in the blood and inhibiting protein synthesis by tumour cells, thus causing them to “starve” to death.
Interestingly, apart from healthcare, asparaginase also has an important role in the food industry as an acrylamide-reducing agent that mitigates the carcinogenic acrylamide accumulated in fried and baked food items.
Asparaginase is mainly derived from two sources, namely the bacteria Escherichia coli (E. coli) and Erwinia chrysanthemi.
Clinical trials incorporating asparaginase were commenced in the early 1970s following the development of large-scale production methods.
Comparison of regimens with or without asparaginase revealed that clinical outcome was significantly improved in those which included asparaginase.
Currently, all treatment protocols for ALL worldwide incorporate asparaginase, which is usually administered via an injection into the buttocks.
Malaysia, too has enjoyed similar accomplishments in the treatment of ALL.
The Malaysia-Singapore (Ma-Spore) Childhood Leukaemia Group recently reported a six-year, event-free survival rate of 96% for patients with standard-risk ALL in their recently published clinical trial, named the Ma-Spore ALL2010 Study.
However, an unexpected event has threatened to derail the successes attained over the last 20 years.
Scientists from the Universiti Malaya Paediatric Oncology Laboratory measuring asparaginase activity. — PROF HANY ARIFFIN(Right) Acute lymphoblastic leukaemia or ALL is a blood cancer that affects a type of white blood cell called lymphocytes. — Wikimedia Commons
Biosimilars not up to mark
For several decades, countries in Asia had access to the best quality asparaginase in the world, manufactured by the Japanese pharmaceutical conglomerate, Kyowa Hakko Kirin.
Unfortunately, in late 2022, Kyowa Hakko Kirin ceased production of E. coli asparaginase, leading to a worldwide shortage of this key drug.
Alternative brand-name asparaginase e.g. from the US costs 50-times more (approximately RM10,000 per dose) and is beyond the means of many healthcare providers in low- and middle-income countries (LMIC).
In response, pharmaceutical companies in China and India began manufacturing biosimilars i.e. compounds with analogous molecular structure, or generic asparaginase to enter the global market.
In January 2023, the United Kingdom-based Bureau of Investigative Journalism warned that more than 70,000 children with leukaemia in 90 countries globally are at risk of being treated with contaminated and low-quality asparaginase.
They reported that some manufacturers continued to sell their products despite being warned that they were below quality assurance standards.
Indeed, many brands did not meet the therapeutic requirements and worryingly, some were even found to contain contaminants, such as bacteria and heavy metals.
So children who are risking their lives to fight leukaemia, now have to fight to ensure they receive good quality asparaginase.
For more than 40 years, we were blessed with high quality asparaginase from Japan.
Now, this key drug is either not affordable (from the US) or of doubtful quality (from India).
There is a real fear of losing up to 15% of patients to relapse or toxicity because of poor asparaginase quality.
Thus, to determine its efficacy, the activity of asparaginase in the blood of children receiving biosimilar asparaginase needs to be serially measured.
With this in mind, paediatric oncologists from Universiti Malaya (UM), the National University of Singapore and St Jude Children’s Research Hospital, US, recently organised a workshop on therapeutic drug monitoring for asparaginase.
Training healthcare staff
Over three days in UM, clinicians and laboratory personnel from seven Asia-Pacific countries were trained to measure plasma levels of asparaginase in their patients.
Monitoring asparaginase activity in patients’ blood samples would indicate whether the drug was efficacious and could adequately destroy leukaemia cells, avoiding under-treatment and risk of disease relapse.
Also, in the workshop, clinicians were trained to draw up an action plan to mitigate asparaginase shortage in their respective countries as well as to start asparaginase monitoring in their hospitals.
These efforts are vital to avoid mistakes such as in Italy, Guatemala and Brazil where the price their patients paid for poor quality asparaginase was a significant increase in ALL relapse rates.
This is just one of the many collaborative efforts undertaken to ensure children in the region continue to have a good chance of cure from cancer.
Additionally, the WHO is piloting the Global Platform for Access to Childhood Cancer Medicines, which will provide an uninterrupted supply of quality-assured chemotherapy drugs to children living in LMICs.
Similar to the Unicef model of providing quality vaccines to LMICs, this platform will assist countries with the selection of good quality medicines, develop treatment standards and build information systems to track that effective care is being provided.
The WHO-St Jude Global Initiative on Childhood Cancer has a target of “60 by 30” (cure rate of at least 60% for all childhood cancers by 2030).
Needless to say, a threat to the supply of a vital cancer medicine such as asparaginase would be a major setback to this goal.
However, over and above the inability to hit slogan targets or maintain historical success rates, the real devastation would be that of losing children to cancers which are curable.
Professor Dr Hany Ariffin is a senior consultant paediatric oncologist and head of Universiti Malaya Medical Centre’s Paediatric Haematology-Oncology and Blood & Marrow Transplantation unit. Professor Dr Allen Yeoh is a senior consultant and head of Paediatric Haematology and Oncology division in Singapore’s National University Hospital. For further information, email starhealth@thestar.com.my. The information provided is for educational and communication purposes only, and it should not be construed as personal medical advice. Information published in this article is not intended to replace, supplant or augment a consultation with a health professional regarding the reader’s own medical care. The Star does not give any warranty on accuracy, completeness, functionality, usefulness or other assurances as to the content appearing in this column. The Star disclaims all responsibility for any losses, damage to property or personal injury suffered directly or indirectly from reliance on such information.
